Ageing and cancer
Challenge: Decipher the functional basis underlying the association between ageing somatic tissues and cancer
Cancer incidence increases dramatically with age and is the leading cause of death in both males and females aged 60-79 years old. Ageing is associated with tissue remodelling and an accumulation of somatic mutations, genome instability, epigenetic alterations, and mitochondrial dysfunction amongst other cellular abnormalities. How distinct ageing processes increase cancer risk at different organ sites remains unclear. No single cellular process associated with an ageing soma sufficiently explains cancer risk across all tissues.
This challenge seeks to understand how ageing-associated molecular changes in somatic cells and immune dysfunction together with endogenous and exogenous environmental factors, impact early cancer initiation in ageing somatic tissues, and organ-specific cancer risk.
Barriers and opportunities
Ageing is associated with multiple aberrations in cellular physiology, immune dysfunction, tissue homeostasis and architecture. Somatic cell dysfunction with age is manifested by genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, altered intercellular communication and stem cell exhaustion. Ageing tissues suffer from extracellular matrix remodelling (ECM) that might permit expansion of mutant clones within normal tissue and an ageing immune system impairs immune surveillance.
No single ageing process explains cancer risk across all tissues suggesting that distinct cellular processes associated with ageing drive cancer risk in different tissues. The multi-faceted impact of ageing on cellular and organ function, the absence of tractable model systems that reflect human longevity and our nascent understanding of clonal evolution of normal cells in ageing tissue and the impact of ageing processes on tissue architecture have together limited our understanding of how ageing increases cancer risk.
New approaches are required to:
Develop functional insights into how ageing contributes to cancer risk
Understand how changes in tissue architecture driven by ageing and prolonged exposures to environmental stimuli might alter clonal dynamics in normal tissue and influence cancer risk
Understand how distinct ageing-associated cellular and immune processes impact early cancer initiation and organ-specific cancer risk
Vision and Impact
Addressing this challenge would provide a deep functional understanding of diverse cellular and immune ageing processes and their functional consequences on organ-specific cancer risk.
Techniques could be developed to understand how alterations in the ECM constrain or promote clonal expansions within normal tissue and how ageing of somatic cells, taking into account environmental exposures, contributes to tumour initiation and promotion. Addressing this challenge will require an interdisciplinary team that could include members with expertise in ageing syndromes and animal modelling, natural ageing processes in human tissue, cellular senescence and mitochondrial function, immunology, extracellular matrix biology, environmental carcinogenesis, and clonal evolution of normal tissue. Applicants should specify their definition of ageing as it relates to the proposed studies, including a rationale for the models selected and/or age range of study participants.
By identifying functional ageing processes driving organ-specific cancer risk, new interventions that lower cancer risk in ageing populations could be developed.